The goal of this project is to develop molecular tools that can be used to aid in the diagnosis and treatment of depression. Medications currently used to treat depression are only effective approximately 50% of the time and few, if any, objective measures exist, which predict response to a given treatment. Thus, the availability of molecular probes to guide the initial choice of treatment and/or to monitor response to treatment at the molecular level (which may occur weeks in advance of clinical response) would offer an enormous advance in the treatment of depression. We will interview, and draw blood from, individuals with Major Depressive Disorder as well as non-depressed control subjects. We will extract RNA from the blood and perform microarray analysis to measure changes in the expression of a large number of genes in response to anti-depressant treatment, as well as differences in the level of expression of these genes, which may be present in affected individuals prior to treatment. This project builds on our previous work looking at gene-expression changes in transgenic mice and animals treated with anti-depressants and will allow us to expand those studies to a clinical setting. It involves a collaboration between basic science researchers in the Division of Molecular Psychiatry, headed by Dr. Ronald Duman, and clinical researchers at three Yaleaffiliated clinics: the Yale Depression Research Clinic, Yale Behavioral Gynecology Clinic, and the VA-CT Neuropsychiatry Clinic. These clinics serve over five hundred patients each year, and include both men and women from a wide variety of ethnic and socio-economic groups. This project will complement ongoing work in the Division of Molecular Psychiatry funded by our NIH Program Project Grant "The Neurobiology of Major Psychiatric Disorders". Ongoing studies using microarray analysis to detect gene-expression changes in the brains of animals treated with anti-depressants and in post-mortem tissue from human subjects with major depressive disorder will enable us to correlate any changes observed in the present study with those occurring in both animal and human brains. Results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, further studies would involve examening differences among different types of depressive disorders and the correlation between gene-expression changes and treatment-response.